Antigen-nonspecific intercellular interactions between T-lymphocytes and antigen-presenting cells (APCs) generate T cell stimulatory signals that generate T cell responses to antigen (Jenkins and Johnson 1993 Curr. Opin. Immunol. 5:361–367). Stimulatory signals determine the magnitude of a T cell response to antigen, and whether this response activates or inactivates subsequent responses to antigen (Mueller et al. 1989 Annu. Rev. Immunol. 7: 445–480).
T cell activation in the absence of costimulation results in an aborted or anergic T cell response (Schwartz, R. H. 1992 Cell 71:1065–1068). One key stimulatory signal is provided by interaction of T cell surface receptors CD28 and CTLA4 with B7 related molecules on APC (e.g., also known as B7-1 and B7-2, or CD80 and CD86, respectively) (P. Linsley and J. Ledbetter 1993 Annu. Rev. Immunol. 11:191–212).
The molecule now known as CD80 (B7-1) was originally described as a human B cell-associated activation antigen (Yokochi, T. et al. 1981 J. Immunol. 128:823–827; Freeman, G. J. et al. 1989 J. Immunol. 143:2714–2722), and subsequently identified as a counterreceptor for the related T cell molecules CD28 and CTLA4 (Linsley, P., et al. 1990 Proc. Natl. Acad. Sci. USA 87:5031–5035; Linsley, P. S. et al. 1991(a) J. Exp. Med. 173:721–730; Linsley, P. S. et al. 1991 (b) J. Exp. Med. 174:561–570).
More recently, another counterreceptor for CTLA4 was identified on antigen presenting cells (APC) (Azuma, N. et al. 1993 Nature 366:76–79; Freeman 1993(a) Science 262:909–911; Freeman, G. J. et al. 1993(b) J. Exp. Med. 178:2185–2192; Hathcock, K. L. S., et al. 1994 J. Exp. Med. 180:631–640; Lenschow, D. J. et al., 1993 Proc. Natl. Acad. Sci. USA 90:11054–11058; Ravi-Wolf, Z., et al. 1993 Proc. Natl. Acad. Sci. USA 90:11182–11186; Wu, Y. et al. 1993 J. Exp. Med. 178:1789–1793).
This molecule, now known as CD86 (Caux, C., et al. 1994 J. Exp. Med. 180:1841–1848), but also called B7-0 (Azuma et al., 1993, supra) or B7-2 (Freeman et al., 1993a, supra), shares about 25% sequence identity with CD80 in its extracellular region (Azuma et al., 1993, supra; Freeman et al., 1993a, supra, 1993b, supra). CD86-transfected cells trigger CD28-mediated T cell responses (Azuma et al., 1993, supra; Freeman et al., 1993a, 1993b, supra).
Comparisons of expression of CD80 and CD86 have been the subject of several studies (Azuma et al. 1993, supra; Hathcock et al., 1994 supra; Larsen, C. P., et al. 1994 J. Immunol. 152:5208–5219; Stack, R. M., et al., 1994 J. Immunol. 152:5723–5733). Current data indicate that expression of CD80 and CD86 are regulated differently, and suggest that CD86 expression tends to precede CD80 expression during an immune response.
Soluble forms of CD28 and CTLA4 have been constructed by fusing variable (v)-like extracellular domains of CD28 and CTLA4 to immunoglobulin (Ig) constant domains resulting in CD28Ig and CTLA4Ig. CTLA4Ig binds both CD80 positive and CD86 positive cells more strongly than CD28Ig (Linsley, P. et al. 1994 Immunity 1:793–80). Many T cell-dependent immune responses are blocked by CTLA4Ig both in vitro and in vivo. (Linsley, et al., (1991b), supra; Linsley, P. S. et al., 1992(a) Science 257:792–795; Linsley, P. S. et al., 1992(b) J. Exp. Med. 176:1595–1604; Lenschow, D. J. et al. 1992, Science 257:789–792; Tan, P. et al., 1992 J. Exp. Med. 177:165–173; Turka, L. A., 1992 Proc. Natl. Acad. Sci. USA 89:11102–11105).
Soluble CTLA4 molecules are effective immunosuppressive agents. There is a need to discover additional soluble CTLA4 molecules for treatments requiring donor-specific and antigen-specific tolerance.